ABSTRACT Long bones are formed and repaired through the process of endochondral ossification. Our goal is to understand molecular mechanisms of endochondral bone growth and apply that knowledge to improve musculoskeletal tissue regeneration and healing. Towards this goal, we made the novel discovery that chondrocyte- and osteoblast-lineage cells express ion channels called GIRKs that control potassium transport across cell membranes and activate intracellular programs after activation of G-protein-coupled receptors. We demonstrate that GIRK subunits are expressed in chondrocyte- and osteoblast-lineage cells, but not osteoclasts. Animals lacking both Girk2 and Girk3 have remarkably longer and denser bones, suggesting greater cartilage and bone formation when Girk2 and Girk3 are absent or inactivated. The central hypothesis of this project is that Girk2 and Girk3 cooperate to regulate chondrocyte and osteoblast survival, proliferation and/or maturation during endochondral bone development. Our specific aims are to: 1) determine how Girk2 and Girk3 regulate growth plate chondrocyte maturation, 2) define how Girk2 and Girk3 contribute to osteoblast-lineage maturation and bone density, and 3) determine if channels formed by Girk2 and Girk3 are required for opioid-induced responses in chondrocytes and osteoblasts. The significance of this work is that Girk2 and Girk3 are potentially druggable targets whose activities and/or expression could be controlled to accelerate long bone growth and healing.